Volume replacement is associated with a diminished osmolar effect of mannitol in patients with acute brain injury.

INTRODUCTION: Animal experiments recently demonstrated that replacing urinary loses with crystalloid diminishes the therapeutic effect of mannitol by reducing the increase in osmolality. We aimed to investigate whether this effect is similarly seen in in brain-injured patients by studying the association between total body fluid balance (TBB) and the osmolar response to mannitol. METHODS: We performed a retrospective cohort study of adult patients with acute brain injury between 2015 and 2021 who received ≥ 2 doses of mannitol within 8 hours and no intercurrent concentrated saline solution. We analyzed the association between the change in TBB (∆TBB) and change in osmolality (∆Osm) before and after mannitol in a linear model, both as univariate and after adjustment for common confounding factors. RESULTS: Of 6,145 patients who received mannitol, 155 patients met inclusion criteria (mean age 60 ± 17 years, 48% male, 83% white). The mean total mannitol dose was 2 ± 0.5 g/kg and the mean change in plasma osmolality was 7.9 ± 7.1 mOsm/kg. Each 1 L increase in ∆TBB was associated with a change of -1.1 mOsm/L in ∆Osm (95% CI [-2.2, -0.02], p = 0.045). The magnitude of association was similar to that of total mannitol dose and remained consistent in an adjusted model and after excluding outliers. CONCLUSIONS: In patients with acute brain injury, a positive TBB is associated with a diminished mannitol-induced increase in plasma osmolality. Future prospective studies are needed to confirm these findings and their influence on the therapeutic effect of mannitol.

Safety of Intravenous Push Valproate Compared with Intravenous Piggyback at a Tertiary Academic Medical Center.

BACKGROUND AND OBJECTIVES: Data are limited regarding the safety associated with administering valproate sodium by intravenous push (IVP) compared with intravenous piggyback (IVPB). The objective of this retrospective pre-post analysis was to compare the safety profile of valproate administration via IVPB from March to May 2022 and IVP from June to August 2022. METHODS: A total of 890 IVPB and 440 IVP administrations were included. The major endpoint of this analysis was the incidence of infusion site reactions (infiltration or phlebitis). RESULTS: The incidence of documented intravenous (IV) site reactions demonstrated minimal differences between both IVPB and IVP administration cohorts. Based on the Naranjo algorithm, all IVPB and IVP infusion site reactions were classified as possible or doubtful. Additional safety endpoints included bradycardia, hypotension, or sedation attributable to valproate sodium administration. Similar safety profiles were observed, including valproate-associated bradycardia, hypotension, and sedation events. All safety events were further classified as possible or doubtful by the Naranjo algorithm. Time from pharmacist verification to valproate administration was also collected. The mean time from pharmacist order verification to valproate administration was significantly faster in the IVP cohort compared to the IVPB cohort. CONCLUSION: IVP valproate administration may be considered safe, allowing for more optimal clinical and operational outcomes in the acute care setting.

Prevalence, risk factors, and outcomes associated with delayed second doses of antibiotics in sepsis at a large academic medical center.

Objective: To evaluate the prevalence, risk factors, and clinical impact of delays in second doses of antibiotics in patients with sepsis. Design: Single-center, retrospective, observational study. Setting: Large teaching hospital. Patients: Adult patients who triggered an electronic sepsis alert in the emergency department (ED), received ≥2 doses of vancomycin or an antipseudomonal beta-lactam, and were discharged with an ICD-10 sepsis code. Methods: We assessed the prevalence of delays in second doses of antibiotics by ≥25% of the recommended dose interval and conducted multivariate regression analyses to assess for risk factors for delays and in-hospital mortality. Results: The cohort included 449 patients, of whom 123 (27.4%) had delays in second doses. In-hospital death occurred in 31 patients (25.2%) in the delayed group and 71 (21.8%) in the non-delayed group (p = 0.44). On multivariate analysis, only location in a non-ED unit at the time second doses were due was associated with delays (OR 2.75, 95% CI 1.20-6.32). In the mortality model, significant risk factors included malignant tumor, respiratory infection, and elevated Sequential Organ Failure Assessment (SOFA) score but not delayed second antibiotic doses (OR 1.19, 95% CI 0.69-2.05). In a subgroup analysis, delayed second doses were associated with higher mortality in patients admitted to non-intensive care units (ICUs) (OR 4.10, 95% CI 1.32-12.79). Conclusions: Over a quarter of patients with sepsis experienced delays in second doses of antibiotics. Delays in second antibiotic doses were not associated with higher mortality overall, but an association was observed among patients admitted to non-ICUs.

Safety of Intravenous Push Levetiracetam Compared to Intravenous Piggyback at a Tertiary Academic Medical Center: A Retrospective Analysis.

INTRODUCTION: Medication administration via intravenous push presents multiple potential advantages; however, there may be an increased risk of adverse drug reactions. In 2020, Brigham and Women's Hospital changed levetiracetam intravenous administration to intravenous push (IVP). OBJECTIVE: The purpose of this analysis was to compare the safety profile of IVP to intravenous piggyback (IVPB) levetiracetam administration. METHODS: This institutional review board-approved, single-center, pre-post analysis was performed between 1 November, 2019 and 30 May, 2020. The electronic health record was used to identify all administrations of intravenous levetiracetam greater than 1000 mg in patients ≥ 18 years old. The major safety outcomes included hypotension, bradycardia, drug-induced sedation, and intravenous site reactions such as phlebitis and infiltration. The major efficiency outcome was the time from pharmacy order verification to first-dose administration. RESULTS: A total of 498 administrations in 162 patients were included in the analysis: 252 administrations in 84 patients in the IVP group and 246 administrations in 78 patients in the IVPB group. The incidence of bradycardia was 7 vs 3 (3.2% vs 1.5%, p = 0.34); hypotension 10 vs 6 (5.2% vs 3.5%, p = 0.44); sedation 21 vs 36 (19.3% vs 27.9%, p = 0.12); and peripheral IV site reactions 0 vs 1 (0% vs 0.6%, p = 0.39) in the IVP vs IVPB groups, respectively. The median time between order verification and first-dose administration was significantly reduced in the IVP vs IVPB group (23.5 vs 55 min, p < 0.001). CONCLUSIONS: Intravenous push levetiracetam administration of doses up to 4000 mg was associated with a similar incidence of cardiovascular, sedation, and infusion site-related adverse events compared to IVPB and resulted in a significant reduction in time to first-dose administration. Intravenous push levetiracetam in doses as high as 4000 mg may be considered safe with appropriate monitoring.

Treatment of Subarachnoid Hemorrhage-associated Delayed Cerebral Ischemia With Milrinone: A Review and Proposal.

Delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage continues to be associated with high levels of morbidity and mortality. This complication had long been thought to occur secondary to severe cerebral vasospasm, but expert opinion now favors a multifactorial etiology, opening the possibility of new therapies. To date, no definitive treatment option for DCI has been recommended as standard of care, highlighting a need for further research into potential therapies. Milrinone has been identified as a promising therapeutic agent for DCI, possessing a mechanism of action for the reversal of cerebral vasospasm as well as potentially anti-inflammatory effects to treat the underlying etiology of DCI. Intra-arterial and intravenous administration of milrinone has been evaluated for the treatment of DCI in single-center case series and cohorts and appears safe and associated with improved clinical outcomes. Recent results have also brought attention to the potential outcome benefits of early, more aggressive dosing and titration of milrinone. Limitations exist within the available data, however, and questions remain about the generalizability of results across a broader spectrum of patients suffering from DCI. The development of a standardized protocol for milrinone use in DCI, specifically addressing areas requiring further clarification, is needed. Data generated from a standardized protocol may provide the impetus for a multicenter, randomized control trial. We review the current literature on milrinone for the treatment of DCI and propose a preliminary standardized protocol for further evaluation of both safety and efficacy of milrinone.